Rift Valley fever virus (RVFV) causes sporadic but devastating outbreaks of severe human disease and widespread morbidity and mortality in livestock. RVFV is a mosquito-borne virus of the Bunyaviridae family (genus Phlebovirus), and the timing of outbreaks is often closely associated with emergence of floodwater Aedes species mosquitoes following periods of extensive heavy rainfall (Schmaljohn and Nichol, Bunyaviridae, p. 1741-1789. In D. M. Knipe and P. M. Howley (ed.), Fields Virology, 5 ed. Lippincott Williams and Wilkins, Philadelphia, Pa., 2007). Although so far confined to Africa and the Arabian Peninsula, RVFV has the potential to spread to other parts of the world, given the presence and changing distribution of competent vectors throughout Europe and the Americas (Chevalier et al., Euro. Surveill. 15:19506, 2010; Elliott, Clin. Microbiol. Infect. 15:510-517, 2009; Turell et al., J. Med. Entomol. 47:884-889, 2010).
Livestock (e.g., sheep, cattle and goats) are particularly susceptible to RVFV disease; outbreaks are characterized by widespread abortion storms and neonatal mortality approaching 100% (Swanepoel and Coetzer, Rift Valley fever, p. 688-717. In J. A. W. Coetzer, G. R. Thomson, and R. C. Tustin (ed.), Infectious Diseases of Livestock with Special Reference to South Africa. Oxford University Press, Cape Town, 1994). Infection in adult animals is associated with lower mortality, but the loss of a large proportion of young animals has serious economic impact. Humans usually become infected after handling aborted materials or other infected animal tissues, or through the bite of an infected mosquito. Although generally self-limiting, human infections can manifest as a serious febrile illness marked by myalgia, arthralgia, photophobia, and severe headache. In a small proportion of individuals, RVFV disease can progress to hepatitis, delayed-onset encephalitis or retinitis, or a hemorrhagic syndrome. Case fatality in severely afflicted individuals can be as high as 20% (Bird et al., J. Am. Vet. Med. Assoc. 234:883-893, 2009). Currently, there are no specific treatments for RVFV infection recommended in humans or other animals.
RVFV has a tripartite negative-sense single-stranded RNA genome. The large (L) segment encodes the viral polymerase. The medium (M) segment encodes the structural glycoproteins, Gn and Gc, as well as non-structural proteins, including a 78 kD protein and NSm, a virulence factor suggested to function by inhibiting apoptosis (Won et al., J. Virol. 81:13335-13345, 2007). The ambisense small (S) segment encodes, in the viral sense, the nucleoprotein (NP) that is required for RNA synthesis, and the non-structural NSs protein in the opposite orientation. NSs is the major RVFV virulence factor and functions to inhibit the host immune response (Bouloy et al., J. Virol. 75:1371-1377, 2001) by generalized downregulation of host transcription (Billecocq et al., J. Virol. 78:9798-9806, 2004; Le May et al., Cell 116:541-550, 2004), post-transcriptional degradation of protein kinase R (PKR) (Habjan et al., J. Virol. 83:4365-4375, 2009; Ikegami et al., Ann. N. Y. Acad. Sci. 1171 Suppl 1:E75-85, 2009), and repression of the interferon-β (IFN-β) promoter (Le May et al., PLoS Pathogens 4:e13, 2008). Previous work has indicated the importance of both NSm (Bird et al., Virology 362:10-15, 2007) and NSs (Barnett et al., J. Virol. 84:5975-5985, 2010; Vialat et al., J. Virol. 74:1538-1543, 2010) in determining virulence in vivo.
The impact of RVFV disease throughout Africa and the Arabian Peninsula, and the potential for viral spread elsewhere, provide strong incentives to develop safe, efficacious, and affordable vaccines. Examples of recently developed candidate vaccines include DNA-vectored (Bhardwaj et al., PLoS Negl Trop Dis 4:e725, 2010; Lagerqvist et al., Virol. J. 6:6, 2009; Lorenzo et al., Vaccine 28:2937-2944, 2010), virus-like particle (VLP) (de Boer et al., Vaccine 28:2330-2339, 2010; Mandell et al., Virology 397:187-198, 2010; Näslund et al., Virology 385:409-415, 2009), replicon particle (Kortekaas et al., J. Virol. 85:12622-12630, 2011), and live attenuated vaccines (Bird et al., J. Virol. 82:2681-2691, 2008; Dungu et al., Vaccine 28:4581-4587, 2010). VLP candidates show promise and remarkable safety, but generally require adjuvant and/or multiple immunizations for complete protection. In comparison, live attenuated vaccines are highly immunogenic, presumably due to viral replication in an immunized host. However, early live attenuated vaccines (Smithburn, MP-12) were associated with teratogenesis and abortion in livestock (Botros et al., J. Med. Virol. 78:787-791, 2006; Hunter et al., Onderstepoort J. Vet. Res. 69:95-98, 2002). More recently, a naturally occurring RVFV mutant (Dungu et al., Vaccine 28:4581-4587, 2010; von Teichman et al., Vaccine 29:5771-5777, 2011) and a reverse-genetics derived candidate (Bird et al., J. Virol. 85:12901-12909, 2011) have been shown to be both safe and efficacious in livestock.